Project Summary: IgE antibodies are essential mediators of allergic reactions. Small amounts of allergen-specific IgE can cause life-threatening anaphylaxis, but anaphylaxis can be prevented by non-specific or low affinity IgE. Understanding the mechanisms that control the production of high affinity and low affinity IgE is thus of outmost importance for the development targeted therapies. Previous work from our laboratory demonstrated that IgE cells do not follow the classical differentiation pathway that has been well described for IgG cells. IgE germinal center cells are transient and apoptotic, and fail to generate long lived plasma cells and functional IgE memory cells. Nevertheless, high affinity IgE can be generated by the sequential switching of IgG1 cells to IgE. The mechanisms that maintain the memory of IgE responses are poorly understood. Long-term antibody responses, typically those involving IgG antibodies, are maintained by memory B cells that are reactivated upon re-exposure to antigen, and by long lived plasma cells. It is clear that the mechanisms of memory of IgE responses must be unique and different from IgG memory. In this application, we will address the long-lasting question of the cellular origin of high and low affinity IgE in memory responses. Ultimately we want to understand what it takes to make pathogenic IgE, and define steps in the process that could be amenable to therapeutic intervention.